Preparation and evaluation of bilayer buccal tablet of atenolol

Views:
 
Category: Education
     
 

Presentation Description

In the present work, i have Prepared bilayer buccal tablets atenolol using carbopol 934p, HPMC K4M, HHPMC 50 cps, HPMC 15 cps as release modifying polymers , further we had conducted simplex design optimization for promising formulation

Comments

Presentation Transcript

PowerPoint Presentation:

“ DESIGN AND EVALUATION OF BUCCAL TABLETS OF ATENOLOL” By Ganesh G Keshavshetti Reg.No.09PT534 Under the guidance of Mr. S.B. Shirsand M.Pharm . (Ph.D.) DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY HKES’S COLLEGE OF PHARMACY GULBARGA 1

PowerPoint Presentation:

INTRODUCTION AND OBJECTIVE In recent years, there has been a growing interest in the use of delivery of therapeutic agent through various transmucosal routes to provide a therapeutic amount of drug to the proper site in body to promptly achieve and then maintain the desired concentration. Drug delivery via buccal mucosa by using bioadhesive polymers i.e., polymers that will attach to the surface coating of tissues, offers such a novel route of drug administration. It provides direct entry of drug molecules into systemic circulation, thus avoiding hepatic first pass effect. The ease of administration and ability to terminate drug delivery when required makes it a potential and attractive route of drug delivery. Atenolol (β-blocker), is a drug used in the management of hypertension . The drug is well absorbed from the gastrointestinal tract, but its oral bioavailability is low (54%) due to extensive first-pass metabolism. Since buccal route bypasses first-pass effect, the dose of atenolol could be reduced by 50%. The physico -chemical properties of atenolol , its suitable half-life (6-7 h) and molecular weight (266.34) make it suitable candidate for administration by buccal route. 2

PowerPoint Presentation:

The objective of undertaken assignment deals with design and evaluation of bilayer buccal tablets of atenolol in order to: Overcome bioavailability related problems (bypassing the first-pass effect) with a possible reduction in the overall dosage of the drug. To reduce dose dependent side-effects and frequency of administration especially in the elderly hypertensive patients. To facilitate administration to those patients suffering from nausea or vomiting, to patients with an upper gastrointestinal tract disease or surgery which affects GIT absorption or to those patients having difficulty in swallowing peroral medications . OBJECTIVE 3

PowerPoint Presentation:

Advantages of Mucoadhesive buccal drug delivery system Ease of administration. Termination of therapy is easy. Permits localization of drug to the oral cavity for prolonged period of time. Can be administered to unconscious patients. Offers an excellent route to systemic delivery of drugs with high first-pass metabolism , thereby offering improved bioavailability. A significant reduction in dose can be achieved and thus reducing dose dependent side effects. Drugs which are unstable in the acidic environment of the stomach or which are destroyed by enzymatic or alkaline environment of the intestine can be administered by this route. Drugs which show poor bioavailability can be administered conveniently. It offers passive system of drug absorption and does not require any activation.

PowerPoint Presentation:

These can be administered to patients with nausea and vomiting, gastrointestinal disease or surgery or swallowing difficulty. Limitations of Buccal Drug Administration Drugs, which irritate the mucosa or have a bitter or unpleasant taste or an obnoxious odour , cannot be administered by this route. Drugs, which are unstable at buccal pH, cannot be administered by this route. Only drugs with small dose requirement can be administered. Drugs contained in the swallowed saliva follows peroral route and advantages of buccal route are lost

PowerPoint Presentation:

Minghetti et al have designed acitretin two layer buccal tablets, which represent a good alternative to topical gel or ointment for the buccal administration of acitretion for local therapy, as the acitretin was maintained in the salivary compartment for at least 5 hrs and good clinical results were obtained. Ikinci G et al have designed the nicotine hydrogen tartrate buccal tablets and reported that bioadhesion properties of buccal tablets can be controlled by changing the polymer type and concentration. Nakhat PD et al have prepared buccoadesive tablets of metoprolol tartrate which shows optimized formulation containing carbopol 934p and methocel K4M in the ratio of 1:1 which showed surface pH values in the range of 6 to 7 and 91.50% cumulative release in 10 hours . Emami J et al have designed the buccal adhesive verapamil tablets containing 53% CP and 13.3% HPMC, which showed suitable release kinetics and adhesive properties and did not show any interaction between polymers and drug. REVIEW OF LITERATURE 6

PowerPoint Presentation:

Gohel MC et al have prepared seven formulations according to the simplex lattice design. The amount of modified guar gum, untreated guar gum and dicalcium phosphate dehydrate were chosen as independent variables and t 80% (time required to 80% drug dissolution) was selected as the dependant variables and a response equation with interaction terms was generated. Patel DM et al have developed carbamazepine floating tablets using melt granulation technique. A simple lattice design was applied to investigate the combined effect HPMC (X 1 ), ethyl cellulose (X 2 ) and Sodium bicarbonate (X 3 ). The floating lag time (Flag), time required for 50% (t 50% ) and 80% drug dissolution (t 80% ) were taken as responses. Results of multiple regression analysis indicated that low level of X 1 , X 2 and high level of X 3 should be used to manufacturing of the tablet formulation with desired in vitro floating time and dissolution. Surya N et al have prepared buccal patches of atenolol using sodium alginate with various hydrophilic polymers like CP 934p, Sodium CMC and HPMC in various proportions and combinations by solvent casting technique and reported that the fabricated patches were sustained for 24 h and obeyed first-order release kinetics. 7

PowerPoint Presentation:

PLAN OF WORK Construction of calibration curves for atenolol in methanol and pH 6.8 phosphate buffer. Preparation of bilayer buccal tablets of atenolol by direct compression method using HPMC 15 cps, 50 cps and K4M along with carbopol 934p in different ratios. Evaluation of buccal tablets of atenolol . Physical parameters: Physical appearance, hardness, thickness, friability, weight uniformity, swelling index and surface pH. Biological parameter: Mucoadhesive strength. Drug content uniformity. In vitro drug release. Short-term stability. 8

PowerPoint Presentation:

Drug-polymer interaction (FTIR). Stability studies of the promising formulations. Simplex design method Based on the results of evaluation data of the fifteen batches of preliminary trial formulations, the constraints for independent variables X 1 (HPMC 15 cps), X 2 ( carbopol 934p) and ( mannitol ) X 3 for direct compression method were fixed. A simplex design method was used for final optimization of atenolol buccal tablets and all the designed eight batches of formulations were evaluated for hardness, thickness, weight variation, friability, swelling index and surface pH; biological parameter- mucoadhesive strength; and other parameters such as drug content uniformity, in vitro release, short-term stability and drug excipient interactions (FTIR). 9

PowerPoint Presentation:

Y (response) = b 1 X 1 + b 2 X 2 + b 3 X 3 + b 12 X 1 X 2 + b 13 X 1 X 3 + b 23 X 2 X 3 + b 123 X 1 X 2 X 3 Where X 1 , X 2 and X 3 represent transformed percentage concentrations of A, B and C respectively. This is an empirical equation that should represent the response surface in the simplex space. The coefficients can be calculated as simple linear combinations of responses. Simplex design method b 1 = y 1 , the response at 100% A (transformed percentage) b 2 = y 2 , the response at 100% B b 3 = y 3, the response at 100% C b 12 = 4(y 12 ) – 2(y 1 +y 2 ), where, y 12 is the response at 50-50 AB b 13 = 4(y 13 ) – 2(y 1 +y 3 ), where y 13 is the response at 50-50 AC b 23 = 4(y 23 ) – 2(y 2 +y 3 ), where y 23 is the response at 50-50 BC b 123 = 27 (y 123 ) – 12(y 12 +y 13 +y 23 ) + 3(y 1 +y 2 +y 3 ) Where, y 123 is the response at 1/3 A, 1/3 B and 1/3 C Simplex design method provides the advantage of changing the quantity of different ingredients in the formulation in a systematic manner, yet keeping their total amount constant. Therefore, this design was chosen in the present study. Seven batches were prepared, one at each vertex, one half way between vertices and one at the center point. A polynomial equation, containing seven terms, may be evolved using the values of dependent and independent variables. 10

PowerPoint Presentation:

Table-1: Materials Used MATERIAL SOURCES Atenolol Gift sample from Rajat Pharmachem Ltd, Ankaleshwar, Gujarat HMPC 15 cps Colorcon Asia Pvt. Limited, Verna, India HPMC 50 cps Colorcon Asia Pvt. Limited, Verna, India HPMC K4M Colorcon Asia Pvt. Limited, Verna, India Carbopol 934p ShinEtsu Chemical Co. Ltd Japan Polyvinyl Pyrrolidine K-30 SD Fine Chem , Mumbai Mannitol (Pearlitol SD-200) SD Fine Chem , Mumbai Aspartame DOW, USA Magnesium stearate SD Fine Chem , Mumbai Ethyl cellulose Arihant Trading Co., Mumbai, India Table-2: Equipments Used Equipment Source Dissolution test apparatus Electrolab , TDT-06N UV- Visible spectrophotometer UV-1700, Shimadzu Hot air oven MC Dalal and Co., Chennai Tablet compression machine Clit, Ahmedabad Hardness tester Monsanto hardness tester Friability test apparatus Riche Rich Pharma , Mumbai Disintegration test apparatus Campbell Electronics, Mumbai Digital balance Shimadzu, ( BL-220H) Stability chamber Osworld , JRIC-11, Mumbai IR spectroscopy 1615 series, Perkin-Elmer 11

PowerPoint Presentation:

DRUG PROFILE Generic Name : Atenolol Molecular Weight : 266.34 Description Solubility: Very slightly soluble in water , freely soluble in dehydrated alcohol, practically insoluble in ether and chloroform. Slightly soluble in dichloromethane. Standard : Atenolol tablets contain not less than 90% and not more than 110% of the labeled amount of atenolol ( C 14 H 22 N 2 O 3 ). Mechanism Action : Atenolol works by competing for receptor site ( β 1 ) on cardiac muscle. This slows down strength of the heart’s contraction and reduces its oxygen requirements and the volume of blood it has to pump. Hypertension (high blood pressure) may be treated with these drugs because of their ability to increase the diameter of blood vessels thus allowing blood flow under less pressure. Pharmacokinetics : Oral bioavailability : 54% Plasma half-life (t 1/2 ) : 6-7 h Plasma protein binding : 6-16% Peak plasma concentration ( C max ) : 2-4 mcg/ml Excretion : Primarily by renal Class : Antihypertensive 12

PowerPoint Presentation:

METHODOLOGY Table: Standard graph of atenolol in methanol ( λ max = 225.6 nm) Concentration (mcg/ml) Absorbance I II III Mean±SD Blank 0.000 0.000 0.000 0.000±0.000 2 0.0861 0.085 0.084 0.085±0.001 4 0.171 0.1712 0.1782 0.174±0.004 6 0.2509 0.2499 0.255 0.252±0.003 8 0.3156 0.3469 0.3474 0.337±0.018 10 0.428 0.410 0.434 0.424±0.012 a=0.001; b=0.0422; r 2 =0.999 Figure 1: Standard calibration curve of atenolol in methanol Table: Standard graph of atenolol in pH 6.8 phosphate buffer ( λ max = 225.7 nm) Concentration (mcg/ml) Absorbance I II III Mean±SD Blank 0.000 0.000 0.000 0.000 ±0.000 2 0.083 0.085 0.084 0.084 ±0.001 4 0.162 0.162 0.170 0.165 ±0.005 6 0.239 0.243 0.242 0.242 ±0.002 8 0.307 0.310 0.310 0.309 ±0.002 10 0.361 0.367 0.366 0.365 ±0.003 a=0.010; b=0.037; r 2 =0.997 Figure 2: Standard calibration curve of atenolol in pH 6.8 phosphate buffer 13

PowerPoint Presentation:

Preparation: Direct compression method has been employed to prepare buccal tablets of atenolol using, HPMC 15cps, HPMC 50cps, HPMC K4M and carbopol 934p as polymers. (in ratio 50:0, 48:2, 46:4, 42:8, 38:12 HPMC:Carbopol of matrix layer) Procedure: All the ingredients including drug, polymer and excipients were weighed accurately according to the batch formulae (Table-3 and 4). The drug is thoroughly mixed with mannitol on a butter paper with the help of a stainless steel spatula. Then all the ingredients except lubricants were mixed in the order of ascending weights and blended for 10 min in an inflated polyethylene pouch. After uniform mixing of ingredients, lubricant was added and again mixed for 2 min. The prepared blend (100 mg) of each formulation was pre-compressed on 10-station rotatory tablet punching machine (Clit, Ahmedabad ) at a pressure of 0.5 ton and turret speed of 2 rpm to form single layered flat-faced tablet of 8 mm diameter. Then, 50 mg of ethyl cellulose powder was added and final compression was done at a pressure of 3.5 tons and turret speed of 2 rpm to get bilayer tablet. Method of Preparation of buccoadhesive tablets: 14

PowerPoint Presentation:

Table 3: Composition of buccal tablets of atenolol Ingredients mg/tablet Formulation code AT 0 AT 1 AT 2 AT 3 AT 4 BT 0 BT 1 BT 2 BT 3 BT 4 CT 0 CT 1 CT 2 CT 3 CT 4   Atenolol 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25   Carbopol 934p --- 2 4 8 12 --- 2 4 8 12 --- 2 4 8 12   HPMC 50 cps 50 48 46 42 38 --- --- --- --- --- --- --- --- --- ---   HPMC 15 cps --- --- --- --- --- 50 48 46 42 38 --- --- --- --- ---   HPMC K4M --- --- --- --- --- --- --- --- --- --- 50 48 46 42 38   Mannitol 14 14 14 14 14 14 14 14 14 14 14 14 14 14 14   PVP K-30 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6   Aspartame 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3   Mg. stearate 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2   Ethyl cellulose 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50   Total 150 150 150 150 150 150 150 150 150 150 150 150 150 150 150   AT – formulation containing HPMC 50 cps; BT – formulation containing HPMC 15 cps ; CT – formulation containing containing HPMC K4M 15

PowerPoint Presentation:

Ingredients mg/tablet Formulation code A B C AB AC BC ABC C * Atenolol 25 25 25 25 25 25 25 25 HPMC 15 cps 40 10 10 25 25 10 20 30 Carbopol 934p 10 40 10 25 10 25 20 15 Mannitol 10 10 40 10 25 25 20 15 Aspartame 3 3 3 3 3 3 3 3 SSF 3 3 3 3 3 3 3 3 PVP K-30 6 6 6 6 6 6 6 6 flavoring agent 3 3 3 3 3 3 3 3 Ethyl cellulose 50 50 50 50 50 50 50 50 Total weight 150 150 150 150 150 150 150 150 Table 4: Composition of Simplex Design formulations of buccal tablets of atenolol 16

PowerPoint Presentation:

Hardness test : Determined by using Monsanto hardness tester. Friability test: Determined by using Roche friabilator (25 rpm for 4 min). Uniformity of weight : The individual weights of 20 tablets were determined by dusting each tablet off and placing it in an electronic balance. The weight data from the tablets were analyzed for sample mean and percent deviation from the mean. The results are summarized in Table-5 and 6. Uniformity of drug content : Five tablets were powdered in a glass mortar and the powder equivalent to 1 mg of drug was placed in a stoppered 25 ml conical flask. The drug was extracted with 10 ml methanol with vigorous shaking on a mechanical gyratory shaker (100 rpm) for 2 h and filtered into 25 ml volumetric flask through Whatman No.1 filter paper (mean pore diameter 1.5 µm) and more solvent is passed through the filter to produce 25 ml. Aliquots of the solution were filtered through 0.45 µm membrane filter disc ( millipore corporation) and analyzed for drug content by measuring the absorbance at 225.6 nm against solvent blank. Evaluation of buccal tablets 17

PowerPoint Presentation:

Surface pH study : The surface pH of the buccal tablets is determined in order to investigate the possibility of any side effects in vivo . As an acidic or alkaline pH may irritate the buccal mucosa, we sought to keep the surface pH as close to neutral as possible. A combined glass electrode is used for this purpose. The tablet was allowed to swell by keeping it in contact with 1 ml of distilled water ( pH 6.8  0.05 ) for 2 h at room temperature. The pH is identified by bringing the electrode into contact with the tablet surface and allowing to equilibrate for 1 min. Swelling Index : The swelling rate of the buccal tablet is evaluated by using of pH 6.8 phosphate buffer. The initial weight of the tablet was determined (w 1 ). The tablet was placed in pH 6.8 phosphate buffer ( 6 ml ) in a petridish , kept in an incubator at 37  1 o C and tablet was removed at different time intervals ( 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 and 9.0 h ), blotted with filter paper and reweighed (w 2 ). The swelling index was calculated by the formula: Swelling index = 100 (w 2 -w 1 ) / w 1 Figure 4: Swelling index study of formulation BT 1 Fig 3: pH examination of buccal tablets using glass electrode 18

PowerPoint Presentation:

Mucoadhesion strength : The apparatus used for testing bioadhesion was assembled in the laboratory (fig.5). Mucoadhesion strength of the tablet was measured on a modified physical balance employing the method described by Gupta et al using bovine cheek pouch as model mucosal membrane .   19 Figure 5: Bioadhesion Testing Apparatus

PowerPoint Presentation:

20 1 2 3 4 5 6 7

PowerPoint Presentation:

21 A double beam physical balance was taken, the left pan was removed. To left arm of balance a thick thread of suitable length was hanged. To the bottom side of thread a glass stopper with uniform surface was tied. A clean glass mortar was placed below hanging glass stopper. In this mortar was placed a clean 500 ml glass beaker, in which placed another glass beaker of 50 ml capacity in inverted position and weighted with 50 gm to prevent floating. The temperature control system involves placing thermometer in 500 ml beaker and intermittently adding hot water in outer mortar filled with water. The balance was so adjusted that left hand-side was exactly 5 gm heavier than the right. Method: The balance adjusted as described above was used for the study. The bovine cheek pouch, excised and washed was tied tightly with mucosal side upward using thread over the base of inverted 50 ml glass beaker. This beaker suitably weighted was lowered into 500 ml beaker, which was then filled with isotonic phosphate buffer (pH 6.8) kept at 37 o C such that the buffer reaches the surface of mucosal membrane and keeps it moist. This was then kept below left hand side of balance. The buccal tablet was then stuck to glass stopper through its backing membrane using an adhesive ( Feviquick ). The 5 gm on right hand side is removed, this causes application of 5 gm of pressure on buccal tablet overlying moist mucosa. The balance was kept in this position for 3 minutes and then slowly weights were increased on the right pan, till tablet separates from mucosal membrane.

PowerPoint Presentation:

The total weight on right pan minus 5 gm gives the force required to separate tablet from mucosa. This gives bioadhesive strength in grams. The mean value of three trials was taken for each set of formulations. After each measurement, the tissue was gently and thoroughly washed with isotonic phosphate buffer and left for 5 minutes before reading a new tablet of same formulation to get reproducible multiple results for the formulation. In vitro mucoadhesion time: The in vitro residence time was determined using a locally modified disintegration apparatus ( Disintegration tester ). The disintegration medium was composed of 200 ml isotonic phosphate buffer pH 6.8 maintained at 37 o C. A segment of bovine cheek pouch , 3 cm long, was glued to the surface of a glass slab, vertically attached to the apparatus. The mucoadhesive tablet was hydrated from one surface using ml of buffer and then the hydrated surface was brought into contact with the mucosal 22 membrane. The glass slab was vertically fixed to the apparatus and allowed to move up and down. The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded. ( all prepared tablets shows residence time more than 12 hrs )

PowerPoint Presentation:

In vitro drug release study : The backing layer of the buccal tablet is attached to glass disk with cyanoacrylate adhesive . The disk is placed at the bottom of the dissolution vessel. Equipment used----------------------Tablet dissolution test apparatus-II (paddle stirrer at 50 rpm ) Dissolution Medium----------------- 200 ml of pH 6.8 phosphate buffer Volume of Sample withdrawn ----- 5 ml Absorbance measured at ----------- 225.7 nm. The in vitro release data was fitted into four kinetic models as follows: Cumulative % drug released vs time (zero order kinetic model). Log cumulative % drug remaining vs time (first- order kinetic model). Cumulative % drug released vs square root of time (Higuchi’s model) Log cumulative % drug released vs log time ( Korsmeyer Peppas equation) 23

PowerPoint Presentation:

Stability studies: Accelerated stability studies were performed at a temperature of 40 ± 2 o C / 75 ± 5% RH over a period of three months (90 days) on the promising buccal tablets of atenolol (formulations BT 1 and C) . Sufficient number of tablets (15) were packed in amber colored rubber stoppard vials and kept in stability chamber maintained at 40± 2 o C / 75± 5% RH. Samples were taken at one month interval for drug content estimation. At the end of three month period, dissolution test was also performed to determine the drug release profiles. The data of drug content and dissolution studies are shown in Tables-12 to 15. Drug- Excipient Interactions Studies : There is always possibility of drug- excipient interaction in any formulation due to their intimate contact. The technique employed in this study is IR spectroscopy. IR spectroscopy is one of the most powerful analytical technique, which offers possibility of chemical identification. The IR spectra of atenolol , carbopol 934p, HPMC 50 cps, HPMC 15 cps, HPMC K4M, magnesium stearate , aspartame, PVP-K30, mannitol , ethyl cellulose and formulations (AT 1, BT 1, CT 1 and C) were obtained by KBr pellet method (Perkin-Elmer series 1615 FTIR Spectrometer). 24

PowerPoint Presentation:

RESULTS Table 5: Evaluation of Buccal tablets of atenolol Formulation code Mean Hardness* (kg/cm2) Mean Thickness* (mm) Mean Weight Variation* (mg) Friability (%) Mean % Drug Content * Mean Surface PH* Mean Swelling Index* (after 9 h) Mean Mucoadhesive Strength* (g) AT 0 3.40±0.10 2.93±0.05 148.1±0.88 0.79±0.01 95.08±0.62 6.23±0.09 22.19±0.05 4.43±0.12 AT 1 3.90±0.10 2.87±0.06 147.9±0.99 0.67±0.01 94.15±2.75 6.26±0.09 34.58±0.60 5.27±0.15 AT 2 4.13±0.15 2.93±0.06 150.6±0.99 0.57±0.01 101.09±4.01 5.76±0.06 52.26±0.97 6.23±0.12 AT 3 4.40±0.27 2.87±0.06 149.6±0.99 0.55±0.00 97.23±0.46 6.54±0.06 57.87±0.98 6.43±0.06 AT 4 4.60±0.10 2.90±0.00 150.1±0.99 0.51±0.01 97.09±0.30 6.63±0.10 70.69±0.64 6.60±0.10 BT 0 3.47±0.10 2.87±0.06 150.7±1.06 0.87±0.03 97.75±0.38 5.87±0.12 29.54±0.09 3.75±0.07 BT 1 3.83±0.23 2.97±0.06 148.6±0.84 0.72±0.98 96.38±1.56 5.73±0.08 40.90±0.89 5.30±0.14 BT 2 3.93±0.12 2.93±0.06 148.7±0.95 0.56±0.02 102.73±0.46 6.56±0.95 42.55±0.56 5.75±0.21 BT 3 4.23±0.06 2.93±0.06 150.5±0.95 0.52±0.87 96.40±0.84 5.23±0.95 57.83±0.99 5.95±0.07 BT 4 4.47±0.06 2.90±0.00 150.2±0.97 0.56±0.67 104.51±0.83 6.77±0.97 78.04±0.98 6.05±0.07 CT 0 3.90±0.10 2.93±0.00 150.1±0.10 0.40±0.01 96.57±2.69 6.35±0.79 43.92±1.07 4.97±0.15 CT 1 4.17±0.15 2.93±0.00 149.8±0.38 0.20±0.03 97.45±0.66 5.95±0.18 69.12±3.35 5.80±0.10 CT 2 4.50±0.10 3.03±0.06 150.0±0.10 0.40±0.04 97.75±1.69 6.77±0.12 78.98±2.28 6.37±0.06 CT 3 4.67±0.15 2.93±0.06 148.8±0.99 0.46±0.01 98.75±0.88 6.61±0.13 81.38±4.12 6.71±0.10 CT 4 5.07±0.15 3.00±0.06 148.4±1.31 0.20±0.00 104.97±2.94 5.69±0.25 88.18±2.34 7.07±0.15 *Average of three determinations 25

PowerPoint Presentation:

Table 6: Evaluation of Simplex Design Formulations of Buccal Tablets of atenolol Formulation code Mean Hardness* (kg/cm2) Mean Thickness* (mm) Weight Variation* (mg) Friability (%) Mean % Drug Content* Mean Surface PH* Mean Swelling Index* (after 9 h) Mucoadhesive Strength* (g) A 4.40±0.10 3.00±0.10 148.7±0.90 0.46±0.0 100.40±1.31 6.73±0.11 73.43±3.37 7.40±0.10 B 5.77±0.15 3.03±0.15 150.3±1.10 0.47±0.0 96.45±2.06 6.15±0.06 119.2±1.48 14.63±0.35 C 3.53±0.06 3 .00±0.10 150.8±0.98 0.27±0.0 100.67±2.85 6.74±0.06 50.03±4.14 7.20±0.20 AB 4.97±0.06 2.97±0.06 149.5±1.02 0.46±0.00 99.77±2.03 5.89±0.04 103.9±4.96 10.8±0.30 AC 4.27±0.12 3.00±0.00 149.7±0.90 0.34±0.0 95.35±2.22 5.96±0.03 54.65±4.19 8.33±0.25 BC 4.77±0.06 3.03±0.12 150.2±0.79 0.39±0.0 99.84±0.36 6.68±0.11 93.02±2.33 11.83±0.21 ABC 4.80±0.10 2.97±0.06 150.2±0.87 0.20±0.0 102.61±0.85 6.79±0.03 82.45±2.52 11.37±0.35 C * 4.63±0.06 3.03±0.12 149.5±1.36 0.47±0.0 97.95±1.22 5.85±0.05 89.85±1.29 8.20±0.10 *Average of three determinations 26

PowerPoint Presentation:

SI.NO Time (h) Cumulative percent drug release * ±SD AT 0 AT 1 AT 2 AT 3 AT 4 BT 0 BT 1 BT 2 BT 3 BT 4 CT 0 CT 1 CT 2 CT 3 CT 4 1 0 00.00 ± 0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 2 0.5 18.43 ±0.87 16.37 ±0.26 16.10 ±0.16 16.25 ±0.42 14.90 ±0.31 28.13 ±1.50 24.33 ±4.40 22.25 ±1.89 20.11 ±0.77 16.84 ±2.25 17.86 ±0.62 16.90 ±0.49 15.97 ±0.44 15.59 ±0.33 14.18 ±0.77 3 1 36.13 ±2.62 30.62 ±0.29 28.30 ±0.47 27.22 ±1.82 25.53 ±2.58 35.58 ±1.61 33.84 ±0.16 31.70 ±0.42 30.21 ±0.93 28.51 ±2.05 30.55 ±0.45 29.01 ±2.31 25.06 ±0.38 25.39 ±0.99 24.09 ±0.35 4 2 52.85 ±1.61 38.43 ±0.72 40.39 ±2.89 36.92 ±0.67 32.30 ±0.28 54.46 ±1.21 51.93 ±2.22 47.32 ±3.36 43.29 ±2.40 40.57 ±4.31 31.46 ±0.81 30.49 ±1.46 25.71 ±0.24 27.17 ±0.25 25.81 ±1.35 5 3 54.17 ±2.66 52.77 ±2.38 48.53 ±4.46 48.89 ±3.27 45.14 ±2.38 63.26 ±4.92 53.92 ±0.33 52.83 ±3.70 48.34 ±1.57 41.74 ±4.24 40.93 ±0.56 40.91 ±3.03 32.45 ±1.59 33.87 ±1.77 32.16 ±2.36 6 4 58.18 ±0.33 56.38 ±3.45 55.48 ±0.55 48.90 ±1.68 48.95 ±2.10 67.99 ±3.81 59.50 ±0.18 55.75 ±1.90 53.92 ±2.50 51.95 ±3.18 56.57 ±0.43 51.33 ±2.60 46.82 ±3.21 42.32 ±1.31 38.04 ±2.02 7 5 58.99 ±0.45 58.16 ±0.32 56.61 ±2.12 52.53 ±2.53 49.91 ±2.82 77.49 ±3.30 63.67 ±1.98 59.67 ±2.10 56.36 ±4.42 53.58 ±4.25 57.76 ±0.53 53.83 ±1.12 51.65 ±0.55 50.38 ±1.95 44.93 ±2.65 8 6 59.81 ±0.27 58.77 ±0.18 57.74 ±2.39 53.75 ±3.26 51.30 ±3.32 81.20 ±4.49 72.89 ±3.20 61.46 ±4.41 58.49 ±4.68 54.66 ±3.73 58.82 ±0.44 57.61 ±0.39 57.54 ±0.48 57.14 ±0.79 55.81 ±1.95 9 7 64.89 ±2.06 57.79 ±0.33 57.03 ±3.39 54.99 ±1.19 53.28 ±1.02 84.45 ±1.34 78.11 ±1.96 64.93 ±0.43 57.94 ±4.37 55.40 ±4.37 59.44 ±0.49 58.59 ±0.35 56.98 ±0.82 57.51 ±1.34 56.43 ±0.34 10 8 77.68 ±3.29 61.31 ±1.35 61.16 ±2.35 56.18 ±0.77 56.02 ±1.77 87.09 ±0.75 82.12 ±2.46 72.53 ±1.28 60.31 ±3.83 57.53 ±2.92 66.67 ±2.72 62.88 ±0.57 59.07 ±0.72 58.11 ±0.38 57.46 ±1.06 11 9 86.43 ±0.87 63.26 ±1.42 62.86 ±3.02 58.33 ±0.67 57.14 ±0.91 93.68 ±2.10 86.45 ±1.42 74.19 ±.57 61.52 ±3.55 60.46 ±2.22 72.52 ±1.48 70.57 ±2.19 63.54 ±0.54 60.88 ±0.22 58.63 ±0.62 Table 7 : In vitro drug release data of formulation *Average of three determinations 27

PowerPoint Presentation:

Figure 6 : Cumulative percent drug released vs time plots (zero order) of formulations AT 0 , AT 1 , AT 2 , AT 3 and AT 4 Figure 7: Cumulative percent drug released vs time plots (zero order) of formulations BT 0 , BT 1 , BT 2 , BT 3 and BT 4 Figure 8: Cumulative percent drug released vs time plots (zero order) of formulations CT 0 , CT 1 , CT 2 , CT 3 and CT 4 28

PowerPoint Presentation:

SI.NO Time (h) Cumulative percent drug release * ±SD A B C AB AC BC ABC C * 1 0 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 00.00 ±0.00 2 0.5 15.78 ±0.69 13.13 ±0.37 20.49 ±0.63 17.10 ±0.52 15.34 ±0.80 18.41 ±1.51 18.83 ±2.12 16.93 ±2.68 3 1 26.54 ±2.27 19.89 ±0.55 24.86 ±0.08 25.69 ±1.32 22.57 ±2.38 31.77 ±2.17 28.74 ±1.43 28.11 ±2.18 4 2 38.35 ±0.12 25.13 ±1.10 34.19 ±1.18 38.39 ±1.52 25.77 ±0.25 53.03 ±2.33 40.87 ±0.91 34.31 ±0.77 5 3 42.10 ±0.26 25.96 ±0.19 52.51 ±1.13 43.87 ±4.86 26.35 ±0.11 56.60 ±0.54 48.22 ±0.27 49.99 ±0.16 6 4 51.14 ±0.52 26.82 ±0.11 55.17 ±1.10 51.29 ±0.79 30.93 ±1.56 58.50 ±1.19 52.51 ±0.47 56.65 ±1.17 7 5 54.78 ±0.47 29.12 ±0.49 59.48 ±0.21 52.09 ±0.23 34.02 ±0.77 60.38 ±1.21 54.99 ±0.21 58.64 ±0.69 8 6 58.41 ±0.52 32.12 ±1.05 63.54 ±0.47 53.87 ±1.96 39.52 ±0.53 64.00 ±0.49 56.32 ±0.65 61.91 ±0.55 9 7 61.03 ±0.52 36.18 ±1.17 73.23 ±1.65 54.19 ±0.73 43.41 ±2.12 69.11 ±1.77 56.52 ±0.25 62.13 ±1.11 10 8 62.52 ±0.44 39.12 ±1.11 81.19 ±1.09 56.35 ±0.56 49.51 ±0.74 72.02 ±0.62 57.44 ±1.54 63.79 ±1.14 11 9 65.01 ±2.17 41.38 ±0.99 89.43 ±1.01 60.15 ±1.20 51.85 ±1.58 74.84 ±2.19 61.99 ±1.32 66.39 ±0.98 Table 8 : In vitro drug release data of Simplex Design Formulations *Average of three determinations 29

PowerPoint Presentation:

Figure 9 : Cumulative percent drug released vs time plots (zero order) of Simplex Design Formulations A, B, C, AB, AC, BC, ABC and C 30

PowerPoint Presentation:

Table 9: Dissolution parameters for the formulations SI. No. Formulation Code t 25% ( h) t 50% ( h) t 70% ( h) t 90% ( h) Cumulative % drug release in 9 h 1. AT 0 0.34 1.51 7.5 --- 86.65 2. AT 1 0.48 2.51 >9 --- 63.26 3. AT 2 0.51 3.06 >9 --- 62.13 4. AT 3 0.54 4.24 >9 --- 58.33 5. AT 4 0.51 3.42 >9 --- 57.14 6. BT 0 0.30 1.48 4.12 8.30 93.68 7. BT 1 0.33 1.57 5.42 --- 86.45 8. BT 2 0.42 2.30 7.42 --- 74.19 9. BT 3 0.45 3.18 >9 --- 69.52 10. BT 4 0.48 3.46 >9 --- 60.46 11. CT 0 0.48 3.36 8.06 --- 72.52 12. CT 1 0.48 3.51 8.45 --- 70.57 13. CT 2 1.00 4.42 >9 --- 63.54 14. CT 3 1.00 5.00 >9 --- 60.88 15. CT 4 1.36 5.39 >9 --- 58.63 Figure 10: Comparison of dissolution parameters (t 25% , t 50% , t 70% , t 90% ) of buccal tablets of atenolol 31

PowerPoint Presentation:

SI. No. Formulation Code t 25% ( h) t 50% ( h) t 60% ( h) t 70% ( h) Cumulative% drug release in 9 h 1. A 0.57 2.20 5.35 --- 65.01 2. B 2.00 --- --- --- 41.38 3. C 0.39 1.40 3.00 6.36 89.43 4. AB 0.57 3.45 8.54 --- 60.15 5. AC 1.45 8.06 --- --- 51.85 6. BC 0.42 1.51 4.42 7.18 74.84 7. ABC 1.09 3.27 8.30 --- 61.99 8. C * 0.51 1.59 5.24 --- 66.39 Table 10: Dissolution parameters for the formulations Figure 11: Comparison of dissolution parameters (t 25% , t 50% , t 70% , t 90% ) of buccal tablets of atenolol 32

PowerPoint Presentation:

Table 11: Kinetic data (‘r’ values ) of the formulations Formulation code Zero Order First Order Higuchi’s Equation Peppas Equation AT 0 0.774 0.078 0.832 0.6536 AT 1 0.767 0.079 0.801 0.7174 AT 2 0.767 0.063 0.823 0.7781 AT 3 0.758 0.079 0.815 0.6790 AT 4 0.797 0.078 0.849 0.7177 BT 0 0.854 0.029 0.900 0.7456 BT 1 0.887 0.006 0.920 0.6616 BT 2 0.823 0.029 0.875 0.7010 BT 3 0.743 0.071 0.803 0.7201 BT 4 0.778 0.046 0.834 0.6754 CT 0 0.875 0.041 0.915 0.7617 CT 1 0.891 0.033 0.930 0.7990 CT 2 0.901 0.041 0.933 0.6536 CT 3 0.899 0.051 0.934 0.7174 CT 4 0.920 0.062 0.952 0.7781 Formulation code Zero Order First Order Higuchi’s Equation Peppas Equation A 0.852 0.037 0.899 0.6536 B 0.847 0.129 0.897 0.7174 C 0.943 0.000 0.967 0.7781 AB 0.785 0.062 0.839 0.6790 AC 0.912 0.097 0.947 0.7177 BC 0.783 0.026 0.838 0.7456 ABC 0.752 0.062 0.810 0.6616 C * 0.815 0.062 0.862 0.7010 33

PowerPoint Presentation:

Table 12: Stability Data of BT 1 formulation at 40ºC/ 75% RH SI. No. Trial No. 1 st day (%) 30 th day (%) 60 th day (%) 90 th day (%) 1. I 98.12 98.51 98.29 98.08 2. II 98.98 99.13 98.80 98.32 3. III 99.84 97.47 97.10 96.23 4. Mean 98.98 98.37 98.06 97.54 5. S.D 0.86 0.84 0.87 1.14 Table 14: Statistical analysis of Drug Content Data for the Stabilityof BT 1 formulation SI. No. Trial No. 1 st day (%) A 90 th day (%) B A-B 1. I 98.12 98.08 0.04 2. II 98.98 98.32 0.66 3. III 99.84 96.23 3.61 4. Mean 98.98 97.54 1.44 5. S.D 0.86 1.14 1.91 Table 13: Stability Data of C formulation at 40ºC/ 75% RH SI. No. Trial No. 1 st day (%) 30 th day (%) 60 th day (%) 90 th day (%) 1. I 102.50 102.24 101.80 101.10 2. II 97.39 97.10 96.81 96.00 3. III 102.13 101.89 101.25 100.84 4. Mean 100.67 100.41 99.95 93.31 5. S.D 2.85 2.87 2.74 2.87 Table 15: Statistical analysis of Drug Content Data for the Stabilityof BT 1 formulation SI. No. Trial No. 1 st day (%) A 90 th day (%) B A-B 1. I 102.50 101.10 1.40 2. II 97.39 96.00 1.39 3. III 102.13 100.84 1.29 4. Mean 100.67 93.31 1.36 5. S.D 2.85 2.87 0.06 ‘t’ = 1.00 (p < 0.05) ‘t’ = 0.60 (p < 0.05) 1 st 34

PowerPoint Presentation:

Trial No. t 50% (h) values A-B t 70% (h) values A-B 1 st day (A) 90 th day (B) 1 st day (A) 90 th day (B) I 1.57 2.03 0.46 5.42 5.48 0.06 II 2.00 2.16 0.16 5.48 5.58 0.10 III 2.06 2.47 0.41 5.56 6.15 0.59 Mean 1.88 2.17 0.34 5.49 5.74 0.25 S.D 0.27 0.26 0.16 0.07 0.36 0.30 Table 17: Statistical analysis of dissolution parameters (t 50%, t 70% ) of stability formulation (BT 1 ) Table 16 : In vitro drug release data of the stability formulation (BT 1 ) * Average of three determinations Figure-12: In vitro drug release profiles of stability formulation (BT 1 ) ‘t’= 0.85 (p < 0.05) ‘t’= 0.62 (p < 0.05) SI. No. Time (h) Cumulative * % drug released * ± S.D at 40±1 0 C 1 st day 30 th day 60 th day 90 th day 1. 0.5 24.33 ± 4.40 24.20 ± 0.98 24.01 ± 4.09 23.84 ± 2.30 2. 1 33.84 ± 0.16 33.69 ± 2.87 33.47 ± 0.16 32.50 ± 3.20 3. 2 51.93 ± 2.22 51.83 ± 2.19 51.44 ± 0.28 50.11 ± 1.92 4. 3 53.92 ± 0.33 53.84 ± 1.28 53.45 ± 2.10 52.89 ± 0.28 5. 4 59.50 ± 0.18 58.94 ± 3.29 58.64 ± 1.29 58.32 ± 0.29 6. 5 63.67 ± 1.98 63.11 ± 0.95 62.85 ± 0.92 62.13 ± 0.89 7. 6 72.89 ± 3.20 72.67 ± 2.47 72.06 ± 1.20 71.90 ± 1.20 8. 7 78.11 ± 1.96 77.93 ± 1.29 77.42 ± 2.39 76.92 ± 2.30 9. 8 82.12 ± 2.46 81.89 ± 0.28 81.42 ± 3.20 80.93 ± 3.23 10. 9 86.45 ± 1.42 86.01 ± 0.18 85.54 ± 0.87 84.72 ± 1.22 35

PowerPoint Presentation:

Table 18 : In vitro drug release data of the stability formulation (C) SI. No. Time (h) Cumulative * % drug released * ± S.D at 40±1 0 C 1 st day 30 th day 60 th day 90 th day 1. 0.5 20.49 ± 0.63 20.10 ± 0.78 19.89±1.20 18.64±1.02 2. 1 24.86 ± 0.08 24.24 ± 1.10 23.64±0.79 22.40±2.10 3. 2 34.19 ± 1.18 35.98 ± 2.10 34.59±0.88 32.01±3.78 4. 3 52.51 ± 1.13 52.06 ± 0.98 51.79±0.19 51.03±1.67 5. 4 55.17 ± 1.10 54.97 ± 0.27 54.79±0.89 53.03±1.54 6. 5 59.48 ± 0.21 59.13 ± 2.10 58.78±2.10 58.12±1.03 7. 6 63.54 ± 0.47 63.03 ± 3.98 62.72±3.22 61.21±0.98 8. 7 73.23 ± 1.65 73.01 ± 0.26 72.68±3.20 71.10±0.35 9. 8 81.19 ± 1.09 80.92 ± 0.25 80.24±0.27 79.03±0.76 10. 9 89.43 ± 1.01 89.12 ± 1.44 88.63±0.29 87.23±1.02 * Average of three determinations Figure-13: In vitro drug release profiles of stability formulation (C) Table 19: Statistical analysis of dissolution parameters (t 50%, t 70% ) of stability formulation (C) Trial No. t 50% (h) values A-B t 70% (h) values A-B 1 st day (A ) 90 th day (B ) 1 st day (A ) 90 th day (B ) I 1.40 2.54 1.14 6.36 6.54 0.18 II 1.50 2.48 0.98 6.03 6.25 0.22 III 1.30 2.24 0.94 6.24 6.33 0.09 Mean 1.40 2.42 1.02 6.21 6.37 0.16 S.D 0.10 0.16 0.11 0.17 0.15 0.07 ‘t’= 1.03 (p < 0.05) ‘t’=0.83 (p < 0.05) 36

PowerPoint Presentation:

DISCUSSION The main goal of this work was to develop new buccoadhesive bilayer tablets of atenolol , an antihypertensive drug (beta blocker), consisting of drug free non- adhesive protective layer (backing layer). The double layered structure design was expected to provide drug delivery in an uni -directional fashion to the mucosa and to avoid loss of drug due to wash out by saliva, release drug immediately to produce a prompt pharmacological action and remain in oral cavity and provide a sustained release of enough drug over an extended period of time. Mucoadhesive buccal tablets of atenolol were prepared by direct compression method using HPMC 15 cps, 50 cps and K4M along with Carbopol 934p in different ratios using ethyl cellulose as backing layer and evaluated for biological, physical and mechanical parameters. According to work plan, the tablets were evaluated for their appearance, thickness, hardness, friability, weight variation, swelling index, surface pH, drug content, mucoadhesive strength, in vitro release, short-term stability and drug excipient interaction. The results of all these evaluations are given in Tables-5 and 6. 37

PowerPoint Presentation:

38 Based on the results of evaluation of the fifteen batches of the above preliminary trial formulations, optimization was done using simplex design method to investigate the combined effect of hydroxypropyl methylcellulose 15cps (X 1 ), carbopol 934p (X 2 ) and mannitol (X 3 ), the in vitro drug release and mucoadhesive strength were taken as response. All the designed eight batches of formulations were evaluated for hardness, thickness, weight variation, friability, swelling index and surface pH; biological parameter- mucoadhesive strength; and other parameters such as drug content uniformity, in vitro release, short-term stability, drug excipient interactions (FTIR). The appearance of buccal tablets was smooth and uniform on physical examination. The hardness of prepared buccal tablets of atenolol was found to be in the range of 3.40 to 5.77 kg/ cm 2 ; hardness increases with increasing carbopol proportion in the formulation. The thickness and weight variation were found to be uniform as indicated by the low values of standard deviation. The thickness and weight of the prepared buccal tablets were found to be in the range of 2.87 to 3.03 mm and 147.9 to 150.7 mg respectively. Friability values less than 1% indicate good mechanical strength to withstand the rigors of handling and transportations.

PowerPoint Presentation:

The drug content of buccal tablets was quite uniform as shown by Table-5 and 6. The average drug content of the buccal tablets was found to be within the range of 95.15 to 104.97 % and the low values of standard deviation and coefficient of variation (< 2) indicate uniform distribution of the drug within the prepared buccal tablets. The surface pH was determined in order to investigate the possibility of any side effects, in the oral cavity as acidic or alkaline pH is bound to cause irritation to the buccal mucosa. Surface pH of all formulations was found to be in the range of 5.23 to 6.79 as shown in Table-5 and 6. Hence it is assumed that these formulations do not cause any irritation in the oral cavity. The swelling profile of different batches of the tablets is shown in Table-5 and 6. These profiles indicate the uptake of water into the tablet matrix, producing an increase in weight. The swelling state of the polymer (in the formulation) was reported to be crucial for its bioadhesive behavior. Adhesion occurs shortly after the beginning of swelling but the bond formed between mucosal layer and polymer is not very strong. The adhesion will increase with the degree of hydration until a point where over-hydration leads to an abrupt drop in adhesive strength due to disentanglement at the polymer/tissue interface. In formulations maximum swelling was seen with the formulation containing HPMC K4M along with 12% w/w carbopol 934p ( CT 4 ). 39

PowerPoint Presentation:

Results indicate that as the concentration of carbopol 934p increases the swelling index increases. The mucoadhesion of all the buccal tablets of varying ratios of polymers were tested and weight required to pull off the formulation from the mucous tissue is recorded as mucoadhesion strength in grams. The mucoadhesivity of buccal tablets was found to be maximum in case of formulation B i.e. 14.63 g. This may be due to fact that positive charges on surface of carbopol could give rise to strong electrostatic interaction with mucous or negatively charged mucus membrane. In vitro release studies were carried out in USP XXIII tablet dissolution test apparatus-II employing paddle stirrer at 50 rpm and 200 ml of pH 6.8 phosphate buffer as dissolution medium. The in vitro dissolution data of all the designed formulations are shown in tables- 7 to 10 and dissolution profiles depicted in figures 6 to 11. From dissolution data it is evident that designed formulations have displayed more than 57.14% drug release in 9 h . In vitro drug release data of all the buccal tablet formulations of atenolol was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetics and according to Higuchi‟s and Peppas equations to ascertain mechanism of drug release. 40

PowerPoint Presentation:

41 The results of linear regression analysis including regression coefficients are summarized in table-11. From the above data it is evident that all the formulations displayed zero-order release kinetics ( r values from 0.7430 to 0.920 ). Higuchi and Peppas data reveals that the drug is released by non- Fickian diffusion mechanism ( r values from 0.4880 to 0.9670 ). The in vitro release parameter values (t 25% , t 50% and t 70% ) displayed by the various formulations range from 0.30 to 1.45 h (t 25% ), 1.40 to 8.06 h (t 50% ) and 4.12 to 9 h (t 70% ) respectively. The formulations BT 1 (containing HPMC 15 cps 48% of matrix layer along with 2% w/w of carbopol 934p of matrix layer) and formulation C (containing 10% of HPMC 15 cps of matrix layer along with 10% w/w of carbopol 934p of matrix layer) were found to be promising, which showed t 25% , t 50% and t 70% values of 0.33, 1.57, 5.42 and 0.39, 1.40, 6.36 h respectively and released 85.45% and 89.43% drug within 9 h respectively. These formulations have displayed good bioadhesion strength ( 5.30 and 7.2 g respectively)

PowerPoint Presentation:

Development of polynomial equations: The amounts of HPMC 15 cps (X 1 ), carbopol 934p (X 2 ) and mannitol (X 3 ) were selected as independent variables in a simplex design method. The time required for 25% (t 25% ), 50% drug dissolution (t 50% ) and mucoadhesive strength were taken as responses. A statistical model incorporating seven interactive terms was used to evaluate the responses. Y (response) = b 1 X 1 + b 2 X 2 + b 3 X 3 + b 12 X 1 X 2 + b 13 X 1 X 3 + b 23 X 2 X 3 + b 123 X 1 X 2 X 3 …(1) Where, The statistical analysis of simplex design method batches was performed by multiple linear regression analysis using Microsoft Excel. The values (Table 20) for t 25% , t 50% and mucoadhesive strength for all the 7 batches (A to ABC) showed a wide variation (i.e., 0.39 to 1.45, 1.40 to 10.45 and 7.20 to 14.63 g respectively). The data clearly indicate that the values of t 25% , t 50% and mucoadhesive strength are strongly dependent on the selected independent variables. The fitted equations relating the responses t 25% , t 50% and mucoadhesive strength to the transformed factor are shown in Equation 2, Equation 3 and Equation 4 respectively. 42

PowerPoint Presentation:

Mucoadhesive strength= 7.4X 1 +14.63X 2 +7.2X 3 +388.99X 1 X 2 +183.92X 1 X 3 +377.7X 2 X 3 +17931.34X 1 X 2 X 3 (R2= 0.3942) ……(2) t 25% = 0.57X 1 +2.0X 2 +0.39X 3 +0.58X 1 X 2 +0.52X 1 X 3 - 1.66X 2 X 3 –14.76X 1 X 2 X 3 (R2=0.4955) …. (3) t 50% = 2.20 X 1 +10.45 X 2 +1.40 X 3 +66.66 X 1 X 2 +5.12 X 1 X 3 +34.82 X 2 X 3 + 422.88X 1 X 2 X 3 (R2=0.4334) ….(4) The relatively higher values (≥0.4) of correlation coefficients for t 25% , t 50% and mucoadhesive strength indicates a good fit i.e., good agreement between the dependent and independent variables. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e., positive or negative). The equation for mucoadhesive strength suggests that the factor X 2 has more significant effect on mucoadhesive strength followed by factor X 1 and X 3 . From the equation 3 and equation 4, it can be concluded that, factor X 1 and X 2 have more important role in prolonging both, t 25% and t 50% . The magnitude of coefficients indicates that factor X 1 and X 2 have more favorable effect on both the dependent variables than factor X 3 also the high value of X 1 X 2 suggests that the interaction between X 1 and X 2 has a significant effect on t 25% and t 25% . From the results of multiple linear regression analysis, it can be concluded that the drug release pattern can be changed by appropriate selection of the X 1 , X 2 and X 3 levels. The promising formulation was selected on the basis of the acceptance criteria for mucoadhesive strength, t 25% and t 50% as mentioned earlier. 43

PowerPoint Presentation:

Formulation Code Transformed fractions t 25% (h) t 50% (h) Mucoadhesive strength (g) X 1 X 2 X 3 A 1 0 0 0.57 02.20 07.40 B 0 1 0 2.00 10.45 14.63 C 0 0 1 0.39 01.40 07.20 AB 0.5 0.5 0 1.14 03.70 108.27 AC 0 0.5 0.5 0.61 03.08 105.33 BC 0.5 0 0.5 0.78 03.08 54.53 ABC 0.33 0.33 0.33 -1.10 03.90 85.61 Table-20: Evaluation of optimized formulations in simplex design method X 1 = amount of HPMC 15 cps, X 2 = amount of carbopol 934p , X 3 = amount of mannitol , t 25% = time required to release 25% drug, t 50% = time required to release 50% drug 44

PowerPoint Presentation:

Drug- excipient interactions were ruled out by IR spectroscopic studies on the samples (BT 1 and C) stored for three months at 40 ± 2 0 C / 75 ± 5% RH. The IR spectrum of the pure drug atenolol displayed characteristic peaks at 3362.04 cm -1 , 1636.69 cm -1 due to N-H and C=O amide group respectively. The peaks of 1240.27 cm -1 and 2972.40 cm -1 are due to alkyl aryl ether linkage and alcoholic –OH group respectively. All the above characteristic peaks of the pure drug were also found in the IR spectrum of the formulation BT 1 (peaks at 3355.12 cm -1 and 1647.26 cm -1 due to - NH and C=O stretching respectively) and formulation C (peaks at 3362.95 cm -1 and 1653.91 cm -1 due to -NH and C=O stretching respectively). The presence of above peaks indicates undisturbed structure of drug in the above formulations. Hence, there are no drug- excipient interactions.. Groups Absorption peaks (cm -1 ) Pure Atenolol BT 1 C NH-stretching 3362.04 3356.12 3362.95 CO-stretching 1636.69 1647.26 1683.91 CN-stretching 1240.27 1244.11 1244.11 CH-stretching 2972.40 2972.40 2973.00 From the stability studies data it can be seen that the drug content of the above two formulations was not significantly effected at 40 ± 2 o C / 75 ± 5% RH after storage for three months. Statistical analysis of the drug content data (‘t’ test ) gives ‘t’ values ranging from 0.60 to 1.03 which are much less compared to the table value of 4.3 (p<0.05). 45

PowerPoint Presentation:

CONCLUSION From the present study, the following conclusions can be drawn: Mucoadhesive buccal tablets of atenolol can be prepared by direct compression method using HPMC 15 cps, 50 cps and K4M along with carbopol 934p as mucoadhesive polymers in different ratios. In prepared buccal tablets of atenolol , ethyl cellulose successfully used as backing layer which provide drug delivery in an uni -directional fashion and avoid loss of drug due to wash out by saliva. All the prepared tablet formulations were found to be good without capping and chipping. All the prepared tablet formulations were found to be good residence time (more than 12 hrs). As the amount of polymer in the tablets increases , the drug release rate decreases , whereas swelling index and mucoadhesive strength increases. 46

PowerPoint Presentation:

47 In all the tablet formulation, 6% PVP-K30 used as binder which showed acceptable hardness of prepared tablets. In vitro residance test for mucoadhesion indicated good mucoadhesive property of the prepared tablets. The promising formulations BT 1 and C have displayed good water absorption, which indicates the prepared tablets showed better swelling ability in presence of little amount of water. All the designed formulations of atenolol buccal tablets displayed zero order release kinetics and drug release follows non- Fickian diffusion mechanism. Short-term stability studies of the promising formulations ( BT 1 and C ) indicated that there are no significant changes in drug content and dissolution parameter values after 3 months at 40 ± 2 o C / 75 ± 5% RH. IR spectroscopic studies indicated that there are no drug- excipient interactions. CONCLUSION

PowerPoint Presentation:

48 Among the 15 formulations, the formulations BT 1 (containing HPMC 15 cps 48% of matrix layer along with 2% w/w of carbopol 934p of matrix layer) were found to be promising, which showed t 25%, t 50% and t 70% values of 0.33, 1.57, 5.42 h respectively and released 85.45% drug within 9 h. The formulation have displayed good bioadhesion strength (5.30 g). From the results of simplex design experiments, formulation C (containing 10% of HPMC 15 cps of matrix layer along with 10% w/w of carbopol 934p of matrix layer) evaluated as the optimized formulation and showed t 25%, t 50% and t 70% values 0.39, 1.40, 6.36 h respectively and released 89.43% drug within 9 h respectively. The formulation have displayed good bioadhesion strength (7.2 g). Results of multiple regression analysis indicated that low level of X 1 , X 2 and high level of X 3 should be used to manufacture the tablet formulation with desired in vitro drug release and mucoadhesive strength. The validity of the derived polynomial equations for dependent variables ( in vitro drug release and mucoadhesive strength) were checked by designing check-point formulations (C * ) which exhibited almost similar values for the predicted response. CONCLUSION

PowerPoint Presentation:

LIST OF ORAL OR POSTER PRESENTATIONS Buccal mucosa as a site for drug delivery . Poster presented at two days national seminar, sponsored by ICMR Bijapur , Karnataka. (PHED-28) Formulation, design of fast dissolving tablets using low and high compressible saccharides . Poster presented at APTICON 15 th national convention, Hydrabad , A.P. (A-74) Design and evaluation of atenolol bilayer buccal tablets . Poster presented at 62 nd Indian pharmaceutical congress, Manipal , Karnataka. (A-267) LIST OF PUBLICATIONS Design and evaluation of atenolol bilayer buccal tablets . Rajiv Gandhi University of Health Sciences J Pharm Sci (Accepted for 1 st issue Mar/Apr 2011). Development and evaluation of mucoadhesive bilayer buccal tablets of atenolol . Asian J Pharm Sci (communicated). Formulation and optimization of mucoadhesive bilayer buccal tablets of atenolol using simplex design method. Indian J Pharm Edu Res (communicated). 49

PowerPoint Presentation:

50

PowerPoint Presentation:

51 Thank you……

authorStream Live Help